A novel two base pair deletion in the factor V gene associated with severefactor V deficiency

We studied a family in which the proband, a 13-year-old boy, had unmeasurab le plasma levels of coagulation factor V antigen and activity. Clinical sym ptoms were severe, with several episodes of haemorrhages in the mucosal tra cts (gastrointestinal, nose and urinary) and recurrent haemarthroses that c aused permanent arthropathy. Sequence analysis of the factor V gene demonst rated the presence of a novel 2 base pair (bp) homozygous deletion in exon 13 at positions 2833-2834. This mutation, present in the heterozygous state in the asymptomatic mother and absent in the healthy brother, introduced a frameshift and a premature stop at codon 900. This would predict the synth esis of a truncated factor V molecule, lacking part of the B domain and the complete light chain. Because of the existence of a surveillance mechanism that selectively recognizes and degrades mRNA molecules carrying premature termination codons, we analysed the relative abundance of mutant vs. wild- type mRNA molecules in the platelets of the heterozygous proband's mother. The mutant mRNA was significantly reduced in amount (mutant/wild-type ratio 0.35). This is the first reported mutation in the factor V gene causing se vere factor V deficiency, the effect of which was quantitatively analysed a t mRNA level.